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Inflammation is a double-edged sword; it plays an important and beneficial role in the body, but it can also be very dangerous, causing damage to the body and ultimately leading to disease and even death! Whether inflammation will be beneficial or harmful depends on its type and duration. In general, there are two distinct categories of inflammation: acute or short term inflammation and chronic or long term inflammation. While short term inflammation plays a beneficial role in the body, long term or chronic inflammation can be very harmful. These harmful effects will be examined in more detail in a subsequent section. First, it is important to discuss the role of inflammation in the body. If inflammation can be so dangerous, why does it occur in the first place?
Inflammation plays a vital role in the repair process following injury or infection. Without inflammation, disease and damage would quickly progress beyond the body’s ability to recover, and death would result quickly. The body initiates the repair process almost instantaneously upon injury. It is a highly intricate process that involves a complex cascade of processes, many of which proceed concurrently, and many different players including cells and soluble factors (chemicals called chemokines and cytokines) that work synergistically with each other in a very specific manner (see Note: What are Cytokines?).
There are five key characteristics of inflammation, which we have all experienced when we get a cut or a sprained ankle: swelling, pain, redness, heat and loss of function. Each of these characteristics is the result of the body’s efforts to protect the damaged area and to speed up healing and repair. More details about these five characteristics are included in Table 1.
The Inflammatory Response:
In a nut shell, inflammation is a system of information with multiple check points where a decision making process must occur. The body reacts to challenges like foreign invaders or trauma much in much the same way that a computer makes decisions based on a “yes” or “no” format. The body’s inflammatory response is controlled by the immune system, and is part of what is called the innate or non-specific defense system. It is referred to as non-specific, because unlike the body’s specific immune defenses, it does not target specific viruses or pathogens; instead, it acts in a non-specific manner to deal with a wide variety of threats or injuries. The inflammatory response is initiated as a response to trauma, chemical agents or microbial pathogens, and is a highly programmed cascade of actions that occurs immediately in order to prevent the spread of pathogens, minimize further damage to cells and tissues and to promote repair and healing.
When damage, trauma or infection occurs, cells in the tissue called mast cells will produce certain chemicals, including histamine. Histamine is a key chemical trigger of the body’s inflammatory response. The presence of histamine and other chemical factors causes the initiation of three key inflammatory processes: vasodilatation (widening of the blood vessels) in the affected area, increased permeability of the blood vessel, and a movement of white blood cells from the blood to the damaged area (Figure 1).
Vasodilation of the blood vessels in the affected or damaged area brings more blood to the affected area. This causes redness and heat, but the main purpose of this is to supply more immune system cells and other factors to aid in healing and repair. Next, the walls of the blood vessels become more permeable, causing plasma to leak out of the blood vessels and into the affected area. This causes swelling or edema, can lead to pain due to increased pressure, and can impede the function of joints or muscles. The reason for this leakage is that the plasma contains proteins and other factors that are critical for the initiation of healing. For example, the plasma contains clotting proteins and other proteins that stimulate the body’s immune system to destroy bacteria.
Finally, white blood cells called phagocytes will move out of the blood vessels and migrate to the affected site. These important immune system cells will consume and destroy bacteria and pathogens the infected area as well as cleaning up dead cells and other cellular debris during the healing process (Figure 1).
The above description outlines how inflammation is initiated and progresses, leading to eventual healing. In most cases, the inflammatory response is then complete, and things go back to their normal state. However, although this short-term inflammatory process is essential for healing and repair, in some cases the inflammation process does not stop, and it continues on in a long term cycle of chronic inflammation.
This chronic inflammation is not beneficial; it can actually cause even more damage and can eventually contribute to the development of various diseases. The same process that the body uses to defend itself during short-term inflammation backfires when it becomes chronic and ends up harming the body. It is much like an army that turns on the citizens and the country it was meant to defend! In fact, many diseases have now been linked to inflammation, for example, heart disease, stroke, diabetes, liver disease, and even obesity, among others! Although acute inflammation is a vital process, scientists and physicians are beginning to understand that there is a very real need to bring a stop to this long- term inflammation.
What are Cytokines?
Cytokines are small protein molecules that play a key role in cell signaling, that is, they act as cellular messengers, with different cytokines providing different messages to cells about how they should act or react in various situations. Cytokines are produced by cells of the nervous system and also by cells of the immune system, especially macrophages. Cytokines act by binding to surface receptors on other cells, where they initiate a specific response. For example, a cytokine may cause a cell to start producing certain proteins or molecules, or even to produce more cytokines. Cytokines may also be inhibitory and reduce the production of proteins or other cytokines. In this way, the interplay of different cytokines is involved in the regulation and progression of various cellular responses in the body, including the inflammatory response.
Cytokines that play key roles in the inflammatory process are often referred to as inflammatory cytokines. Cytokines can be further broken down into three general categories: chemokines, interleukins and lymphokines. Chemokines are chemicals that attract cells to other cells or a certain area. For example, chemokines are responsible for attracting phagocytes from the blood stream to damaged areas as part of the inflammatory response. Interleukins (abbreviated as IL) were initially described as cytokines produced by leukocytes, but now this category includes a broad range of different signaling molecules involved in the immune response. Many interleukins play a very important role in the mediation of inflammation in the body. Finally, lymphokines are produced by cells called lymphocytes, and are generally involved in the body’s immune response.
The inflammation process is highly complex, however, in general, we can think of inflammation as being divided into short-term and long-term types. If short-term inflammation is beneficial and long term inflammation is unhealthy, the key question is: at what stage does the balance tip? When does inflammation turn from being beneficial to harmful? And most importantly, when should we intervene? For example, if one were to intervene immediately upon the onset of inflammation, theoretically one would be preventing the body from doing its job of protection! This is where the checkpoints come in.
These checkpoints involve feedback and actions from the body’s immune system, which is the great orchestrator of the inflammatory process. At some stage in the inflammatory process, the body’s immune system will decide, based on the evidence available and feedback from key cells, that a certain checkpoint has been reached and will proceed with a specific course of action based on this information. It is these check points that ultimately determine the fate of the inflammatory process.
Unfortunately, as of now, no definite signs or symptoms have been identified that could be used to indicate that a critical checkpoint has been reached and that the balance is about to tip from beneficial to harmful inflammation. This knowledge would certainly make the lives of physicians much easier as they would be better able to identify at what precise point to intervene. Fortunately, biological chemistry comes to the rescue as various biomarkers or “markers of inflammation” have been identified that can be used to help us make this decision. Whilst these markers do not provide a perfect solution, they are a very useful aid in making the decision of how and when to intervene with treatment for an inflammatory condition. Measurement of various biomarkers like NF-KB, CRP, COX, LOX, IL-6 and others (which will be discussed in greater detail in a later section) as well as the presence of various cells and inflammatory gene products are useful markers that are used in the decision of when to act in the treatment of inflammation.
In the pharmaceutical world we have a class of drugs called non steroidal anti-inflammatory drugs (NSAID’s) that are often used to treat inflammation. These include drugs like the commonly used over- the-counter ibuprofen or the more powerful COX-2 inhibitors like Celebrex. Unfortunately, these drugs are associated with many unpleasant side-effects, including gastrointestinal problems or bleeding, heartburn and even kidney or cardiovascular complications. In fact some of these drugs, like Vioxx for example, have been withdrawn from the market. Fortunately, the natural world offers powerful and effective yet safe alternatives which can meet the challenges of inflammation.
Unlike the pharmaceutical drugs that act solely on a “silver bullet” model, meaning that they usually have only one mechanism of action, natural products often have multiple mechanisms of action. This is important because inflammation is a process that acts through numerous pathways. Therefore, dealing with only one pathway will never address the situation effectively; it is not going to put out all of the fires. Generally, the more pathways that are blocked, the more effective the treatment is likely to be. Moreover, natural products tend to be less potent but more “balanced” in their action because they often contain additional molecules that support the major compounds in performing their actions.